Thrombosis remains one of largest causes of mortality and morbidity in the western world. This study seeks to identify and understand key components involved with proper platelet function and subsequently to develop therapies to reduce the mortality associated with aberrant platelet function. There is an intimate relationship between inflammation and thrombosis. For example, inflammatory diseases, such as CVD and sepsis, cause aberrant platelet activation, leading to thrombosis and/or death. The mechanisms that control the liaison between inflammation and hemostasis are poorly defined, and thus this liaison remains a gap in our knowledge. It is known that platelets maintain vascular integrity at sites of inflammation, and consequently inflammatory diseases, such as CVD and sepsis, cause aberrant platelet activation often leading to death. P-selectin initiate's primary contact between platelets and leukocytes and/or endothelial cells and consequently, several clinical trials have been targeted at controlling inflammation via p-selectin, but success has been elusive. Early attempts to solve this challenge have focused on p-selectin interactions with ligands, rather than the potential for redundancy in function. This application represents a new approach to developing this promising target into treatment. We have cloned a platelet surface receptor called triggering receptor expressed in myeloid cells (TREM) like transcript-1, or TLT-1, that is found in mice and humans. TLT-1 is abundant, specific to platelets and megakaryocytes, and like p-selectin, stored in the platelet 1-granules. The soluble form of TLT-1 (sTLT-1) significantly enhances platelet aggregation and actin polymerization in platelets and endothelial cells; and Treml1 null mice show distinct phenotypic overlap with p- selectin null mice. The overlap includes: prolonged bleeding times, delayed neutrophil migration, higher basal neutrophil counts and hemorrhage in response to the Shwartzman model of vasculitis. These phenotypic similarities suggest that TLT-1 function complements that of p-selectin. We hypothesize that TLT-1 mediation of early cytoskeletal rearrangements complements p-selectin's function of initial adhesion of platelets to endothelial cells, and possibly leukocytes, thereby potentiating their ability to respond to both hematological and immunological cues. To test this hypothesis we have developed the following three specific aims. AIM 1: Define the mechanism by which sTLT-1 increases actin polymerization, AIM 2: Define the role of TLT-1 in inflammation and thrombosis. AIM 3: Develop the TLT-1/p-selectin (CD62P) double null mouse (DNTP) model. Our laboratory, having identified TLT-1and developed many TLT-1 reagents is the best suited to delineate TLT-1 function and to translate TLT-1's association with p-selectin from basic biology into clinical significance.